16-81889235-ATG-GTT

Variant names:

• chr16-81889235-ATG-GTT
• NM_002661.5:c.829_831delATGinsGTT
• PLCG2 p.Met277Val

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002661.5(PLCG2):​c.829_831delATGinsGTT​(p.Met277Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M277L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

Genes affected

PLCG2 (HGNC:9066): (phospholipase C gamma 2) The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]

PLCG2 Gene-Disease associations (from GenCC):

• autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• familial cold autoinflammatory syndrome 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002661.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.829_831delATGinsGTT	p.Met277Val	missense	N/A	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.829_831delATGinsGTT	p.Met277Val	missense	N/A	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.829_831delATGinsGTT	p.Met277Val	missense	N/A	NP_001412679.1	P16885

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.829_831delATGinsGTT	p.Met277Val	missense	N/A	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.1073_1075delATGinsGTT		non_coding_transcript_exon	Exon 9 of 20
	PLCG2	ENST00000902427.1		c.829_831delATGinsGTT	p.Met277Val	missense	N/A	ENSP00000572486.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-81922840;